DESCRIPTION:(provided by applicant) Interneurons are integral components of the neural circuits in the spinal cord that control posture and movement. Among the diverse array of spinal interneurons are cell-types that make direct connections with motor neurons and modify their excitability. In the course of our studies of interneuron patterning and specification in the developing spinal cord, we have identified two classes of early embryonic interneurons (INs), V1 and VO INs, which are likely to synapse directly with motor neurons. V1 and VO INs are marked by the expression of En1 and Evx1, respectively. In this proposal, we will determine the cardinal features of V1 and VO INs in order to define their exact relationship to physiologically identified cell types in the adult spinal cord. We will use transsynaptic tracers and paired cell recordings to directly test whether VO INs constitute a subset of crossed reflex interneurons that synapse with contralateral motor neurons. We will test our hypothesis that V1 INs differentiate into Renshaw cells and Ia inhibitory interneurons, by physiologically characterizing the descendants of En1-expressing neurons in spinal cord slice preparations. In addition, we will undertake functional studies to determine the role that V1 INs play in locomotor reflexes by selectively ablating them. We will also silence Renshaw cells in vivo,thereby defining for the first time the role of recurrent inhibition in locomotor behavior. Finally, we will examine whether V1 INs form topologically ordered connections with pools of motor neurons, and determine when and how these connections become organized. These studies will provide valuable insights into the development and organization of circuits in the spinal cord that control locomotor behavior, and will lay the groundwork for strategies to treat spinal cord injury and degeneration.